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Department of Chemistry Garner Research Group

Research in the Garner lab focuses on the development of new enabling chemistries and the synthesis of biologically active molecules. In this context, our intellectual activities may be viewed as architecture (design and construction) on the molecular scale. Chemical synthesis (the discipline associated with building molecular structures) is the common element that underlies all of our research endeavors.

Current research projects include the development of new methodology for the convergent synthesis and site-specific modification of proteins as well as the application of the asymmetric [C+NC+CC] coupling reaction to biologically active pyrrolidine-containing targets.

Research highlights from the Garner Lab

Solid Phase Synthesis of ω-aspartic Thioacid Containing Peptides

1-s2.0-S0040403915008734-fx1

Joseph, R.; Morales-Padilla, M.; Garner, P. Tetrahedron Letters
 2015, 56, 4302.

The Fmoc-based solid phase synthesis of unprotected ω-aspartic thioacid containing peptides is demonstrated. The method involves the novel use of a silyl ester as a carboxylate surrogate for mild peptide bond formation in the presence of a reactive ω-aspartyl thioester. The resulting peptide thioacids may be used in N-glycoligation and other thioacid-mediated conjugation reactions.

Solid Phase Synthesis and Ligative Processing of Photocaged Aziridine-2-carbonyl-terminated Peptides

1-s2.0-S0040403915001392-fx1

Murray, C.; Dryer, F. B.; Garner, P. Tetrahedron Letters
2015, 56, 3636.

A general synthesis of N-terminal aziridinyl-2-carbonyl (Azy) peptides has been developed aided by the photolabile o-nitrophenylethyl protecting group. This method enables the synthesis of unprotected Azy-terminated peptides incorporating ionizable groups using solid phase techniques followed by photorelease of the free N-terminal Azy moiety. The resulting Azy peptides undergo Cu(II)-mediated ligation with thioacids to give Azy-embedded peptides, providing a handle for site-specific modification of the peptide.

 

A Concise [C+NC+CC] Coupling-Enabled Synthesis of Kaitocephalin

Garner, P.; Weerasinghe, L.; Van Houten, I.; Hu, J., Chem. Comm. 2014, 50, 4908.
Weerasinghe, L.; Van Houten, I.; Hu, J.; Garner, P. J. Chem. Comm. 2014, 50, 4908.

A 15-step synthesis of the iGluR antagonist kaitocephalin from aspartic acid is reported. The linchpin pyrrolidine ring of the target molecule is efficiently assembled with in a single operationvia an asymmetric [C+NC+CC] reaction.

 

Catalytic Asymmetric Exo-Selective [C+NC+CC] Reaction

Joseph, R.; Murray, C.; Garner, P., Org. Lett. 2014, 16, 1550.

Joseph, R.; Murray, C.; Garner, P. Org. Lett. 2014, 16, 1550.

A catalytic asymmetric version of the exo-selective [C+NC+CC] reaction is reported. This multicomponent reaction utilizes a readily prepared achiral glycyl sultam as the “NC” component and commercially available catalyst components. The method can be applied to a variety of aldehydes (“C” component) and activated alkenes (“CC” component) to provide substituted pyrrolidines in good yields and high enantioselectivities. Of particular note is the ability to employ labile enolizable aldehydes (e.g., acetaldehyde and propionaldehyde) in this reaction.

 

Rapid Formation of N-Glycopeptides via Cu(II)-Promoted Glycosylative Ligation

Rapid Formation of N-Glycopeptides via Cu(II)-Promoted Glycosylative Ligation
Joseph, R.; Dyer, F. B.; Garner, P. Org. Lett. 2013, 15, 732.

Herein is described the chemoselective Cu(II)-HOBt promoted chemical ligation of glycosylamines and peptide thioacids to give N-glycosylated peptides. The method is distinguished from other chemical approaches to peptide N-glycosylation in that (1) it can be employed in the presence of unprotected N-terminal and Lys side chain amines; (2) it is remarkably fast, going to completion in under 30 min; and (3) it produces glycopeptides without attendant aspartimide formation.

 

[C+NC+CC] Coupling-Enabled Synthesis of Influenza Neuramidase Inhibitor A-315675

[C+NC+CC] Coupling-Enabled Synthesis of Influenza Neuramidase Inhibitor A-315675
Garner, P.; Weerasinghe, L.; Youngs, W. J.; Wright, B.; Wilson, D.; Jacobs, D. Org. Lett. 2012, 14, 1326.
An efficient synthesis of the neuramidase inhibitor A-315675 is reported. The fully functionalized pyrrolidine core of the target is assembled in one pot via an exo-selective asymmetric [C+NC+CC] coupling reaction.

 

Aziridine-Mediated Ligation and Site-Specific Modification of Unprotected Peptides

Aziridine-Mediated Ligation and Site-Specific Modification of Unprotected Peptides
Dyer, F. B.; Park, C.-M.; Joseph, R.; Garner, P. J. Am. Chem. Soc. 2011, 133, 20033.

A synthesis of aziridine-containing peptides via the Cu(II)-promoted coupling of unprotected peptide thioacids and N–H aziridine-2-carbonyl peptides is reported. The unique reactivity of the resulting N-acylated aziridine-2-carbonyl peptides facilitates their subsequent regioselective and stereoselective nucleophilic ring-opening to give unprotected peptides that are specifically modified at the ligation site. The aziridine-mediated peptide ligation concept is exemplified using H2O as the nucleophile, producing a Xaa–Thr linkage (where Xaa can be an epimerizable and hindered amino acid). The overall process is compatible with a variety of unprotected amino acid functionality, most notably the N-terminal and Lys side chain amines.